Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale

Andreas Hallqvist, Johanna Svensson, Linn Hagmarker, Ida Marin, Tobias Rydén, Jean-Mathieu Beauregard, Peter Bernhardt, Andreas Hallqvist, Johanna Svensson, Linn Hagmarker, Ida Marin, Tobias Rydén, Jean-Mathieu Beauregard, Peter Bernhardt

Abstract

177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).

Keywords: 177Lu-DOTATATE; PARP inhibitor; olaparib; somatostatin positive tumor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Manually drawn VOI on SPECT/CT in (a) transversal view (b) sagittal view and (c) coronal view. (d) Tumour ROI and background ROI on the corresponding planar geometrical mean image.
Figure 2
Figure 2
The absorbed dose rate of 177Lu-DOTATATE versus time after administration (post injection, p.i.) for: (a) tumour tissue, (b) bone marrow, and (c) kidney.
Figure 3
Figure 3
The median relative absorbed dose versus the time after treatment start with 177Lu-DOTATATE for the bone marrow (blue line), kidney (red line), and tumour (yellow line). Panel (a) shows the first 4 weeks after the start of treatment, while panel (b) focuses on the first 25 h after the start of treatment.
Figure 4
Figure 4
The median tumour-to-normal tissue absorbed dose ratio (TND) for the bone marrow and kidney during 177Lu-DOTATATE treatment. Panel (a) shows the first 4 weeks after the start of treatment, while panel (b) focuses on the first 25 h after the start of treatment.
Figure 5
Figure 5
The ratio between TNDBM for the time interval 24 h to 28 days compared to the obtained TNDBM from start of treatment to infinity for the 17 patients. The median value of 136% (patient 6) is marked with a dotted red line.

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